Multiscale Modeling of Blood Flow and Platelet Mediated Thrombosis
血流和血小板介导的血栓形成的多尺度建模
基本信息
- 批准号:9032130
- 负责人:
- 金额:$ 68.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-05-01 至 2021-01-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAddressAdhesionsAdoptedAgonistAlgorithmsAnticoagulationAntiplatelet DrugsArteriesBenchmarkingBindingBiochemicalBiologyBiomechanicsBloodBlood CirculationBlood Coagulation FactorBlood PlateletsBlood VesselsBlood flowCardiovascular DiseasesCardiovascular PathologyCardiovascular systemCause of DeathCerealsCessation of lifeChemicalsClinicalCoagulation ProcessCodeCommunitiesComplexComputer SimulationCoronary ArteriosclerosisCoupledCouplingCytoplasmCytoskeletonDataDatabasesDepositionDevelopmentDevicesEngineeringEvaluationEventExperimental ModelsFilopodiaGrowthHealth Care CostsHemostatic AgentsHigh Performance ComputingHybridsIn VitroLeadLengthLifeLiquid substanceMeasurementMeasuresMechanicsMediatingMembraneMethodologyModelingMolecularOutcomePatientsPatternPlatelet ActivationPlatelet aggregationProcessPropertyProteinsProtocols documentationPseudopodiaQuality of lifeRiskSchemeSeriesShapesSoftware ToolsStimulusStressSurfaceTechnologyTherapeuticTherapeutic EmbolizationThrombinThrombosisThrombusTimeTissuesTranslatingVascular Diseasesbasebiomechanical modelburden of illnesscomputing resourcescostdesignfluid flowhemodynamicsimprovedinjuredinnovationinterestmen who have sex with menmicroscopic imagingmolecular dynamicsmolecular scalemortalitymulti-scale modelingmultidisciplinarynanoscalenext generationnovelparticlepublic health relevancereceptorresearch studyresponseshear stresssimulationtoolworking group
项目摘要
DESCRIPTION (provided by applicant): Cardiovascular diseases remain the leading cause of death in the developed world, accounting for near 30% of all deaths globally and 35% in the US annually. Coronary artery disease (CAD) with its associated thrombotic risk is responsible for 1 of 6 deaths in the US. Coincidentally, implantable blood recirculating devices, which have provided lifesaving solutions to patients with severe cardiovascular diseases, are burdened with thrombosis and thromboembolic complications, mandating complex life-long anticoagulation. The mechanisms underlying vascular disease processes and device-related thrombotic complications are intertwined. Thrombosis in vascular disease is potentiated by the interaction of blood constituents with an injured vascular wall and the non-physiologic flow patterns generated in cardiovascular pathologies initiate and enhance the hemostatic response by chronically activating the platelets. Similarly, device thrombogenicity is induced by pathological flow fields and contact with foreign surfaces. Upon activation platelets undergo complex biochemical and morphological changes. The coupling of the disparate spatio-temporal scales between molecular level events and the macroscopic transport represents a major modeling and computational challenge, which requires a multidisciplinary integrated multiscale numerical approach. Continuum approaches are limited in their ability to cover the smaller molecular mechanisms such as filopodia formation during platelet activation. Utilizing molecular dynamics (MD) to cover the multiscales involved is computationally prohibitive. In this application we offer
to develop a comprehensive state-of-the-art multiscale numerical methodology that will be able to bridge the gap between the macroscopic transport and the ensuing molecular events. We will use an integrated Dissipative Particle Dynamics (DPD) and Coarse Grained Molecular Dynamics (CGMD) approach that allows platelets to continuously change their shape and synergistically activate by a biomechanical transductive linkage chain, interact with other blood constituents and clotting factors, aggregate, and interact and adhere to the blood vessels and devices. In this multiscale model, a mechanotransduction CGMD bottom platelet activation model is embedded into a DPD blood flow top model. The dynamic stresses of the macroscale model will be interactively translated to the micro to nanoscale model of the intra-platelet associated intracellular events. The model predictions will be validated in vitro in a carefully designed set of experiments. This will be achieved according to the following specific aims: We will develop a mechanotransduction model of platelet mediated thrombosis where a top/macro-scale model of flow-induced thrombogenicity using DPD at the µm-length and ms-time scales, in which multiple flowing platelets interact with each other and blood vessel walls or devices, will be fully coupled with a bottom/micro-scale model using CGMD at the nm-length and ps-time scales, in which platelets with multiple intracellular constituents evolve during activation as platelet lose their quiescent discoid shape and filopodia grow. The top and bottom models will be interfaced such that the hemodynamics will interactively respond to platelet shape change upon activation and platelet aggregation and thrombus is formed. The effect of modulating platelet mechanical properties via antiplatelet agents will be modeled as well. All model aspects will be validated in vitro in a series of carefully designed experiments characterizing the mechanical properties of platelets and using blood flow experiments where conditions leading to flow induced platelet activation will be replicated, as well as experiments where platelet-wall and
platelet device interactions will be measured and where platelets will be pretreated with modulating agents. These data will be used to fine tune the large number of model parameters involved in this multiscale simulation and for validating the model predictions. An independent 3rd party evaluation of the model credibility is also included as an integral part of the project. e will also concentrate on the development of efficient algorithms adapted for ultra-scalable large HPC clusters to reduce prohibitive computation costs, so as to bring such ambitious large multiscale simulations within the reach of the multiscale modeling community at large and enable to adopt it to other relevant modeling needs and interests. To further enable these technologies, large sharable data base will be created where software tools, numerical codes, model and experimental data and protocols will be deposited and guidance will be provided for using them. The leaders of the project will be active in various MSM consortium working groups to further disseminate the project outcomes and share them with the modeling community. The methodology proposed represents a paradigm shift in the burgeoning field of multiscale simulations and its application to solving complex clinical problems at the interface of engineering and biology. Predicting the progression of arterial thrombosis under circulation conditions, providing tools for improved pharmacological management as compared to existing empirics-based treatments, and providing a modeling tool for developing the next generation of devices with reduced thrombogenicity may lead to reduced mortality rates, improved patients' quality of life, and an overall reduction of the financial burden of the ensuing healthcare costs.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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DANNY BLUESTEIN其他文献
DANNY BLUESTEIN的其他文献
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{{ truncateString('DANNY BLUESTEIN', 18)}}的其他基金
Biomechanical Approaches and Technologies for Enhancing TAVR Outcomes
提高 TAVR 效果的生物力学方法和技术
- 批准号:
10201598 - 财政年份:2018
- 资助金额:
$ 68.94万 - 项目类别:
Biomechanical Approaches and Technologies for Enhancing TAVR Outcomes
提高 TAVR 效果的生物力学方法和技术
- 批准号:
10449331 - 财政年份:2018
- 资助金额:
$ 68.94万 - 项目类别:
A Novel Polymeric Valve for Transcatheter Aortic Valve Replacement
用于经导管主动脉瓣置换的新型聚合物瓣膜
- 批准号:
9344868 - 财政年份:2017
- 资助金额:
$ 68.94万 - 项目类别:
A Novel Polymeric Valve for Transcatheter Aortic Valve Replacement
用于经导管主动脉瓣置换的新型聚合物瓣膜
- 批准号:
10221033 - 财政年份:2017
- 资助金额:
$ 68.94万 - 项目类别:
A Novel Polymeric Valve for Transcatheter Aortic Valve Replacement
用于经导管主动脉瓣置换的新型聚合物瓣膜
- 批准号:
9903032 - 财政年份:2017
- 资助金额:
$ 68.94万 - 项目类别:
A Novel Polymeric Valve for Transcatheter Aortic Valve Replacement
用于经导管主动脉瓣置换的新型聚合物瓣膜
- 批准号:
10464978 - 财政年份:2017
- 资助金额:
$ 68.94万 - 项目类别:
Multiscale Modeling of Blood Flow and Platelet Mediated Thrombosis
血流和血小板介导的血栓形成的多尺度建模
- 批准号:
9265504 - 财政年份:2016
- 资助金额:
$ 68.94万 - 项目类别:
Multiscale modeling of blood flow and clotting in cardiovascular devices
心血管设备中血流和凝血的多尺度建模
- 批准号:
8114454 - 财政年份:2011
- 资助金额:
$ 68.94万 - 项目类别:
Multiscale modeling of blood flow and clotting in cardiovascular devices
心血管设备中血流和凝血的多尺度建模
- 批准号:
8258220 - 财政年份:2011
- 资助金额:
$ 68.94万 - 项目类别:
Optimizing Cardiovascular Device Thromboresistance for Eliminating Anticoagulants
优化心血管装置的抗血栓能力以消除抗凝剂
- 批准号:
8016863 - 财政年份:2010
- 资助金额:
$ 68.94万 - 项目类别:
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